Glycogen synthase kinase-3β inhibition alleviates activation of the NLRP3 inflammasome in myocardial infarction

J Mol Cell Cardiol. 2020 Dec:149:82-94. doi: 10.1016/j.yjmcc.2020.09.009. Epub 2020 Sep 28.

Abstract

Inflammasome-promoted sterile inflammation following cardiac damage is critically implicated in heart dysfunction after myocardial infarction (MI). Glycogen synthase kinase-3 (GSK-3β) is a prominent mediator of the inflammatory response, and high GSK-3 activity is associated with various heart diseases. We investigated the regulatory mechanisms of GSK-3β in activation of the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in a rat model with successful induction of MI on days 2-28. An in vitro investigation was performed using newborn rat/human cardiomyocytes and fibroblast cultures under typical inflammasome stimulation and hypoxia treatment. GSK-3β inhibition markedly improved myocardial dysfunction and prevented remodeling, with parallel reduction in the parameters of NLRP3 inflammasome activation after MI. GSK-3β inhibition reduced NLRP3 inflammasome activation in cardiac fibroblasts, but not in cardiomyocytes. GSK-3β's interaction with activating signal cointegrator (ASC) as well as GSK-3β inhibition reduced ASC phosphorylation and oligomerization at the tissues and cellular levels. Taken together, these data show that GSK-3β directly mediates NLRP3 inflammasome activation, causing cardiac dysfunction in MI.

Keywords: ASC; Cardiac fibroblasts; Glycogen synthase kinase 3; Myocardial infarction; NLRP3 inflammasome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CARD Signaling Adaptor Proteins / metabolism
  • Enzyme Activation / drug effects
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Glycogen Synthase Kinase 3 beta / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Indoles / pharmacology
  • Inflammasomes / metabolism*
  • Inflammation / pathology
  • Male
  • Maleimides / pharmacology
  • Myocardial Infarction / metabolism*
  • Myocardial Infarction / physiopathology
  • Myocardial Ischemia / enzymology
  • Myocardial Ischemia / pathology
  • Myocardial Ischemia / physiopathology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Multimerization / drug effects
  • Rats, Sprague-Dawley
  • Vascular Remodeling / drug effects

Substances

  • CARD Signaling Adaptor Proteins
  • Indoles
  • Inflammasomes
  • Maleimides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Protein Kinase Inhibitors
  • Pycard protein, rat
  • SB 216763
  • Glycogen Synthase Kinase 3 beta